The ability to heal by forming scars is essential for mammalian systems to survive wounding after injury. Normally, wound healing is a continuous process extending over a one-to-two-year period. The process can be conceptually divided into three fundamentally distinct stages. The first stage is an intensely degradative phase called the inflammatory stage. It occurs immediately after injury and provides a means to remove the damaged tissues and foreign matter from the wound. Two-to-three days later, as fibroblasts from the surrounding tissue move into the wound, the repairing process enters its second stage, the proliferation and matrix synthesis stage. The fibroblasts in the wound proliferate and actively produce macromolecules, such as collagen and proteoglycans, which are secreted into the extracellular matrix. The newly-synthesized collagen fibrils are cross-linked by lysyl oxidase and provide structural integrity to the wound. During this stage, fibroblasts also contract the intact collagen in order to reduce the surface area of the wound. This second stage lasts about three weeks. In the final, remodeling stage, the previous randomly-organized collagen fibril is aligned in the direction of mechanical tension and becomes more organized so that the mechanical strength of the wound area can be increased. The repair process is accomplished when the chemical and physical barrier functions of the skin are restored.
Normal wound healing follows a well-regulated course. However, imbalances may cause abnormal scars to form. For example, if the biosynthetic phase continues longer than necessary or degradation of collagen decreases, hypertrophic scars may form. These scars cause problems ranging from aesthetic deformity to severe limitation of motion. Hypertrophic scars more frequently occur among children and adolescents, suggesting that growth factors may influence the development of this type of scar. Hypertrophic scars are especially common in patients who have burns or wounds that heal by secondary intention. Another type of excess scar is the keloid. In this disorder, the cells appear to lack sensitivity to normal feedback signals. They are larger than hypertrophic scars and grow in an unregulated way, tending to invade normal tissue surrounding the wound. They rarely disappear spontaneously and often recur after surgical excision. The management of these scars remains a major unsolved clinical problem.
Existing therapy for hypertrophic scars and keloids includes surgery, mechanical pressure, steroids, x-ray irradiation and cryotherapy. There are many disadvantages associated with each of these methods. Surgical removal of the scar tissue is often incomplete and can result in the development of hypertrophic scars and keloids at the incision and suture points. Steroid treatments are unpredictable and often result in depigmentation of the skin. X-ray therapy is the only predictably effective treatment to date; however, because of its potential for causing cancer, it is not generally recommended or accepted.
Compositions comprising tripetides, tetrapeptides and pentapeptides have been shown to inhibit biosynthesis of collagen and may be used to treat diseases caused by excess accumulation of collagen (Mitsubishi Chem., Japanese Patent Nos. 52083545, Jul. 12, 1977, and 52025768, Feb. 25, 1977). The effects of applying silastic sheets onto the surface of hypertrophic scars was studied and shown to shrink and soften scar tissue. [Ohmori, S. Aesthetic Plastic Surgery 12: 95-99 (1988)].
Despite the various treatments presently available, there is no widely accepted and predictably effective means for preventing or treating wound scars, such as hypertrophic scars or keloids.